Parkinson's disease (PD) is a late onset neurodegenerative disease that affects about 5% of the population by age 85 (Melrose et al. 2006). PD affects a wide range of brain regions, from brainstem to cerebral cortex, though the diagnostic motor symptoms arise from loss of dopaminergic neurons in the substantia nigra. To study early stages of the disease that are pre-diagnostic in humans, a progressive animal model is needed. Such an animal model would develop pathology in all the brain regions affected in humans in the same order. While Parkinson's disease is primarily sporadic and of unknown etiology, rare genetic forms may provide means for development of appropriate animal models. We are using mice transgenic for a-synuclein, the first gene linked to familial PD (Polymeropoulos et al. 1997), to study the mechanism by which the mutant protein causes disease, and to develop better mouse models for PD. Mouse transgenics that overexpress a-synuclein under the regulation of heterologous promoters develop disease in regions of the nervous system not affected in PD (Cabin et al. 2005; Melrose et al. 2006). We hypothesize that the mechanism by which a-synuclein causes neurodegeneration will be the same in all types of neurons. When overexpressed in motor neurons, a-synuclein causes an axonopathy that can be studied in the easily accessible sciatic nerve (Cabin et al. 2005; Giasson et al. 2002; Lee et al. 2002), though spinal cord motor neurons are not affected in PD. The endogenous human a-synuclein promoter is being used to drive appropriate expression of the protein to develop a new generation of transgenic mice that will develop disease that more closely resembles PD. The a-synuclein promoter does not drive over-expression in spinal cord (Cabin et al., in prep.), and regulates expression in brain in a pattern similar to that of the endogenous mouse a- synuclein promoter. In addition, mouse a-synuclein protects against against the pathological effects of the human mutant protein; an A53T human a-synuclein transgene causes earlier disease onset in mice lacking endogenous a-synuclein (Cabin et al. 2005). Thus transgenes driven by the human a- synuclein promoter will be studied on both wild type and a-synuclein null backgrounds. We propose using a cell culture system to investigate the mechanism of this protective effect of mouse a- synuclein. Developing a mouse model that better recapitulates Parkinson's disease will provide a means to study the early stages of the disease that affect the enteric and olfactory nervous systems, stages that occur in humans before loss of a majority of nigral dopaminergic neurons causes the motor symptoms required for diagnosis. Such a mouse would be useful for developing tests for earlier diagnosis, and for testing drugs meant to prevent disease progression. Better understanding of the mechanism of a-synuclein pathogenicity would, in the long term, aid in development of such drugs.